Sympathetic excitotoxicity in sepsis: pro-inflammatory priming of macrophages by norepinephrine

Abstract

In the history of medicine, the interaction between mind and body has been repeatedly proposed. However, the influence of the nervous system on the immune regulation has, until now, drawn little attention. In this regard, the adrenergic system has been explored, and mainly catecholamine-mediated anti-inflammatory effects have been described. These inhibitory effects of epinephrine and norepinephrine were found to be mediated by beta2-adrenoceptors expressed on mononuclear cells. Recently, the role of the parasympathetic nervous system in the local anti-inflammatory reflex has been investigated. Stimulation of the vagus nerve decreases the pro-inflammatory response of macrophages via alpha7-cholinergic receptors. Thus, both the sympathetic and parasympathetic nervous systems are thought to work hand in hand in their anti-inflammatory responses. Here we discuss the deteriorating effects of the release of norepinephrine in sepsis. We have discovered that organ dysfunction in severe sepsis is mediated at least in part by an increase in pro-inflammatory cytokine release from Kupffer cells, which is caused by a priming via gut-derived norepinephrine. The sympathetic nervous system and gut-derived norepinephrine mediate the pro-inflammatory effects by activating alpha2A-adrenoceptor on Kupffer cells. In this review, we will focus on the differential function of the noradrenergic system on local and systemic inflammatory responses and the possibilities of the modulation of sympathetic outflow by centrally active inhibitors such as the novel peptide ghrelin or NMDA-receptor blockers. Furthermore, we will introduce the new concept of "sympathetic excitotoxicity in sepsis" characterized by the neurogenic priming of the systemic pro-inflammatory response.

Human Ghrelin Ameliorates Organ Injury and Improves Survival after Radiation Injury Combined with Severe Sepsis

“…It is now widely accepted that the nervous system reflexively regulates the inflammatory response in real time (44,45). Our previous studies have indicated that the release of the sympathetic neurotransmitter, norepinephrine (NE), from the small intestine is increased in sepsis, and that NE potentiates endotoxin-induced TNF-α upregulation via the A subtype of α 2 -adrenoceptors expressed on the surface of Kupffer cells (44). Ghrelin has sympathoinhibitory properties.…”

“…Moreover, ghrelin activates the vagus nerve and vagal blockade abolishes ghrelin-induced feeding and growth hormone secretion (49). Stimulation of the vagus nerve can attenuate systemic inflammatory responses rapidly through inhibiting the activation of macrophages and endothelial cells (44,45). Our previous studies have shown that the antiinflammatory effect of ghrelin requires the intact vagus nerve, as vagotomy prevents its beneficial effects in sepsis and gut ischemia reperfusion injury (18,50).…”

Posttraumatic Stress Disorder and Cardiometabolic Disease

“…Sympathetic excitotoxicity entails neurogenic priming of the systemic proinflammatory response. PTSD-associated SNS arousal may also activate the RAAS and promote inflammatory pathways [80]. …”

Controversial Issues Concerning Norepinephrine and Intensive Care Following Severe Traumatic Brain Injury

“…Subsequently, lymphopenia with a mismatch between T helper and T cytotoxic lymphocytes with sustained neutrophil activity [55] develops. Released proinflammatory cytokines, in turn, can influence central noradrenergic pathways [56]. Overall, norepinephrine interferes with immunocompetence [57] which could contribute to evolving multiorgan failure [58] (Figures 4a, 4b, and 4d).…”

“…In addition, b-adrenergic activation controls release of pro-and antiinflammatory cytokines [44,65,66] and contributes to depressed cellmediated inflammation by stimulating the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor that mediates antiinflammatory actions [67], as well as inhibiting NF-kB and activating I-kBa [68,69]. At low norepinephrine concentrations (»20 nM), a 2 receptor activation stimulates TNF-a and IL-1b production in hepatic Kupffer cells which is inhibited by high concentrations via b 2 -adrenergic receptors [56]. b 2 -adrenergic stimulation also induces cellular immunosuppression by downregulating various receptors on stimulated human peripheral blood mononuclear cells [70].…”